Risk of cardiovascular and cerebrovascular events and mortality in patients with migraine receiving prophylactic treatments: An observational cohort study.

INTRODUCTION: This study quantified risks of cardiovascular, cerebrovascular, and mortality events among patients with migraine receiving prophylaxis. METHODS: Patients with migraine aged 18-65 years were identified from 2010 through 2015 within a United States administrative claims database. Topiramate initiators during follow-up were propensity score-matched separately to anticonvulsant, cardiovascular treatment, antidepressant, and other prophylactic treatment initiators. Incident outcomes were identified, and hazard ratios were calculated comparing outcome occurrence among topiramate initiators relative to each comparator. A case-control analysis was nested within the full migraine cohort, and odds ratios quantified the association between outcomes and use or non-use of individual prophylactic treatments (anticonvulsants, serotonin norepinephrine reuptake inhibitors, beta blockers, antihypertensives, tricyclic antidepressants, and other prophylactic treatments). RESULTS: The cohort included 119,243 patients with migraine. The matched topiramate initiators had a lower mortality risk versus antidepressant (hazard ratio: 0.44, 95% CI: 0.24, 0.83) and anticonvulsant initiators (hazard ratio: 0.45, 95% CI: 0.25, 0.84). In the case-control analysis, increased risks of several outcomes were observed with all prophylactic treatments relative to non-use of that treatment (odds ratios range from 1.54 to 7.90, and 95% CIs exclude 1.0) except for topiramate and calcium channel blockers. CONCLUSIONS: Although increased risks for several outcomes were observed with certain prophylactic treatments, the treatments other than topiramate likely represent markers for outcome risk factors that developed or progressed after cohort entry, rather than being a direct effect of the treatments. Factors including migraine severity, frequency, and other treatment indications should be considered in future migraine prophylactic treatment safety assessments.

Validation of current procedural terminology codes for rotavirus vaccination among infants in two commercially insured US populations.

PURPOSE: We validated procedure codes used in health insurance claims for reimbursement of rotavirus vaccination by comparing claims for monovalent live-attenuated human rotavirus vaccine (RV1) and live, oral pentavalent rotavirus vaccine (RV5) to medical records. METHODS: Using administrative data from two commercially insured United States populations, we randomly sampled vaccination claims for RV1 and RV5 from a cohort of infants aged less than 1 year from an ongoing post-licensure safety study of rotavirus vaccines. The codes for RV1 and RV5 found in claims were confirmed through medical record review. The positive predictive value (PPV) of the Current Procedural Terminology codes for RV1 and RV5 was calculated as the number of medical record-confirmed vaccinations divided by the number of medical records obtained. RESULTS: Medical record review confirmed 92 of 104 RV1 vaccination claims (PPV: 88.5%; 95% CI: 80.7-93.9%) and 98 of 113 RV5 vaccination claims (PPV: 86.7%; 95% CI: 79.1-92.4%). Among the 217 medical records abstracted, only three (1.4%) of vaccinations were misclassified in claims-all were RV5 misclassified as RV1. The medical records corresponding to 9 RV1 and 15 RV5 claims contained insufficient information to classify the type of rotavirus vaccine. CONCLUSIONS: Misclassification of rotavirus vaccines is infrequent within claims. The PPVs reported here are conservative estimates as those with insufficient information in the medical records were assumed to be incorrectly coded in the claims. Copyright © 2016 John Wiley & Sons, Ltd.

Development and evaluation of an algorithm to identify users of Prolia(®) during the early postmarketing period using health insurance claims data.

PURPOSE: The goal of this study is to develop and validate an algorithm to identify Prolia(®) users within a health insurance claims database. METHODS: Patients with a denosumab-specific or nonspecific administration claim during the early period of Prolia availability in the USA (June 1, 2010 to March 31, 2012) were classified as definite, probable, possible, and nonusers of Prolia using an algorithm consisting of nine different components based on claims patterns consistent with Prolia use. Medical record review confirmed a sample of definite, probable, and possible users and the positive predictive value (PPV) was estimated. RESULTS: The PPV of the claims-based algorithm components varied (17.8-95.8%). Requiring claims for a bone or cartilage disorder or osteoporotic fracture after excluding claims for cancer prior to a denosumab-specific administration code gave the highest PPV (95.8%), followed by requiring a Prolia National Drug Code on the same claim as a denosumab-specific or nonspecific administration code (88.2%). Among the 87 confirmed Prolia users, osteoporosis diagnoses were seen more frequently in the medical record than in claims (83% vs 62%). CONCLUSIONS: Prolia users are most accurately identified with administration code claims in conjunction with claims for Prolia National Drug Code and bone disorder treatment and diagnosis codes. Osteoporosis diagnoses may be under-recorded in claims data. The algorithm may require reassessment as uptake for more recently approved indications increases.

Infection outcomes in patients with rheumatoid arthritis treated with abatacept and other disease-modifying antirheumatic drugs: Results from a 10-year international post-marketing study.

OBJECTIVE: To evaluate risk of infections requiring hospitalization and opportunistic infections, including tuberculosis, in patients with rheumatoid arthritis (RA) treated with abatacept versus conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) and other biologic/targeted synthetic (b/ts) DMARDs. METHODS: Five international observational data sources were used: two biologic registries (Sweden, Germany), a disease registry (USA) and two healthcare claims databases (Canada, USA). Crude incidence rates (IRs) per 1000 patient-years, with 95 % CIs, were used to estimate rate ratios (RRs) comparing abatacept versus csDMARDs or other b/tsDMARDs. RRs were adjusted for demographic factors, comorbidities, and other potential confounders and then pooled across data sources using a random effects model (REM). RESULTS: The data sources included 6450 abatacept users, 136,636 csDMARD users and 54,378 other b/tsDMARD users, with a mean follow-up range of 2.2-6.2 years. Across data sources, the IRs for infections requiring hospitalization ranged from 16 to 56 for abatacept, 19-46 for csDMARDs, and 18-40 for other b/tsDMARDs. IRs for opportunistic infections were 0.4-7.8, 0.3-4.3, and 0.5-3.8; IRs for tuberculosis were 0.0-8.4, 0.0-6.0, and 0.0-6.3, respectively. The pooled adjusted RR (95 % CI), only reported for infections requiring hospitalization, was 1.2 (0.6-2.2) for abatacept versus csDMARDs and 0.9 (0.6-1.3) versus other b/tsDMARDs. CONCLUSIONS: Data from this international, observational study showed similar hospitalized infection risk for abatacept versus csDMARDs or other b/tsDMARDs. IRs for opportunistic infections, including tuberculosis, were low. These data are consistent with the known safety profile of abatacept.

Real-world effectiveness of elexacaftor/tezacaftor/ivacaftor on the burden of illness in adolescents and adults with cystic fibrosis.

Background: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) has been shown to be safe and efficacious in people with cystic fibrosis (CF) aged ≥2 years. Here, we describe results from an observational study assessing change in burden of illness following initiating ELX/TEZ/IVA in real-world settings. Methods: This US-based, multicenter, observational study used data from electronic medical records to evaluate real-world burden of illness before and after ELX/TEZ/IVA initiation in people with CF aged ≥12 years heterozygous for F508del and a minimal function mutation (F/MF) or an uncharacterized CFTR mutation. Endpoints included absolute change from baseline in percent predicted forced expiratory volume in 1 s (ppFEV1), body mass index (BMI) and BMI-for-age z-score, glycated hemoglobin (HbA1c), and numbers of pulmonary exacerbations (PEx). Results: Overall, 206 people with CF were enrolled (mean [SD] age 22.5 [11.1] years; 192 [93.2%] with F/MF genotype). Mean follow-up was 15.6 (SD, 1.6) months. Improvements in ppFEV1 (7.3 [95% CI: 5.7, 8.8] percentage points) were observed from baseline through follow-up. Increases in BMI (1.40 [95% CI: 1.07, 1.77] kg/m2) and BMI-for-age z-score (0.14 [95% CI: 0.00, 0.28]) were also observed from baseline at 12 months. The estimated annualized rate of any PEx was 1.31 at baseline and 0.61 over follow-up (rate ratio 0.47 [95% CI: 0.39, 0.55]), with annualized rates of PEx requiring antibiotics and hospitalizations of 0.55 and 0.88 in the baseline period and 0.12 and 0.36 over follow-up (rate ratios 0.22 [95% CI: 0.15, 0.31] and 0.41 [95% CI: 0.32, 0.51]), respectively. Absolute change in HbA1c was -0.22 (95% CI: -0.38, -0.06) from baseline through follow-up. Conclusions: ELX/TEZ/IVA treatment was associated with improved lung function, increased BMI, reduced frequency of PEx, and improved (i.e., reduced) HbA1c. These results confirm the broad clinical benefits of ELX/TEZ/IVA seen in clinical trials and show the potential for ELX/TEZ/IVA to improve markers of glucose metabolism.

Reduction in healthcare resource use through 24 months following sinus surgery with steroid-eluting implants in chronic rhinosinusitis patients with and without nasal polyps: a real-world study.

OBJECTIVE: To investigate the impact of steroid-eluting implants after endoscopic sinus surgery (ESS) on health care resource use (HCRU) in chronic rhinosinusitis patients with (CRSwNP) and without (CRSsNP) nasal polyps. METHODS: This retrospective, observational cohort study using real-world evidence data included adult patients with CRS who underwent ESS in 2015-2019 with at least 24 months of data before and after ESS. Patients who received implants were matched to patients who did not based on a propensity score developed using baseline characteristics and NP status. HCRU was compared between cohorts within each CRSwNP and CRSsNP subgroup using chi-square tests (binary variables). RESULTS: The implant cohort in the CRSwNP subgroup had fewer all-cause outpatient (90.0% vs. 93.9%, p < .001) and all-cause otolaryngology (64.3% vs. 76.4%, p < .001) visits as well as fewer endoscopy (40.5% vs. 47.4%, p = .005) and debridement (48.8% vs. 55.6%, p = .007) procedures than the non-implant cohort. The implant cohort in the CRSsNP subgroup had fewer all-cause outpatient (88.9% vs. 94.2%, p < .001) and all-cause otolaryngology (53.5% vs. 74.4%, p < .001) visits as well as fewer endoscopy (31.8% vs. 41.7%, p < .001) and debridement (36.7% vs. 53.4%, p <.001) procedures than the non-implant cohort. Revision sinus surgery was reduced in the implant cohort in both subgroups, and reached statistical significance in the CRSwNP subgroup (3.8% vs. 6.0%, p = .039) but not in the CRSsNP subgroup (3.6% vs. 4.2%, p = .539). CONCLUSIONS: Overall, patients receiving implants had lower HCRU for 24 months after sinus surgery independent of nasal polyp status, and revision surgery was reduced in CRSwNP patients. These findings provide additional evidence that long-term reductions in HCRU may be achieved with steroid-eluting implant use during sinus surgery.What is known on this topicPatients with chronic rhinosinusitis with nasal polyps (CRSwNP) have a disproportionately higher burden of disease and consume greater healthcare resources than chronic rhinosinusitis patients without nasal polyps (CRSsNP).CRSwNP patients represent approximately 30% of CRS patients who undergo surgery, but their clinical course is disproportionally complicated by disease recurrence and revision surgery.Steroid-eluting sinus implants have been shown in clinical trials to improve short-term postoperative outcomes after endoscopic sinus surgery (ESS) in CRS patients in general.A recent real-world evidence study reported that steroid-eluting sinus implants following ESS were associated with a reduction in HCRU in CRS patients followed for 18 months, but the impact of implants on HCRU in CRSwNP and CRSsNP patients separately remains unknown. What this study addsIn this observational study, reduced HCRU was observed in CRSwNP and CRSsNP patients who receive steroid-eluting sinus implants.Use of implants in CRSwNP and CRSsNP patients was associated with a significant reduction in healthcare visits (all-cause outpatient, all-cause otolaryngology), and sinus procedures (endoscopy, debridement).Revision surgery was significantly reduced in the implant cohort of CRSwNP patients and trended lower in the implant cohort of CRSsNP patients.Use of implants had no significant impact on all-cause ER/urgent care visits or sinus-related imaging.

Real-world evidence analysis of the impact of steroid-eluting implants on healthcare resource use among chronic rhinosinusitis patients undergoing sinus surgery.

OBJECTIVE: To compare healthcare resource use (HCRU) in patients undergoing sinus surgery with or without steroid-eluting sinus implants. METHODS: A retrospective, observational cohort study using real-world evidence data (OM1, Inc, Boston, MA, USA) was conducted on adult patients with chronic rhinosinusitis (CRS) with or without nasal polyps who underwent endoscopic sinus surgery between 2014 and 2019 and had at least 18 months of data both before and after surgery. Patients receiving implants ("implant cohort") were matched to patients who did not receive implants ("non-implant cohort") based on a propensity score developed using baseline characteristics. Chi-square for binary variables and analysis of variance tests for continuous variables were applied to compare HCRU measures. RESULTS: Comparison of the implant (N = 1983) and non-implant (N = 1983) cohorts during the 18-month follow-up period demonstrated significantly lower HCRU in those receiving implants, including all-cause outpatient visits (94.3% vs. 96.6%, p < .001), all-cause otolaryngologist visits (47.3% vs. 59.6%, p < .001) and all cause ER/urgent care visits (9.2% vs. 11.8%, p = .007), as well as sinus-related endoscopies (39.1% vs. 43.8%, p = .003). Although not statistically significant, fewer patients in the implant cohort had undergone repeat surgeries (4.6% vs. 5.3%, p = .273). CONCLUSION: Patients with steroid-eluting sinus implants had lower HCRU over a post-operative period of 18 months. These findings support the contention that reductions in HCRU may be achieved using steroid-eluting implants during sinus surgery.What is known on this topicChronic rhinosinusitis (CRS) causes severe symptoms that lead to poor quality of life.Endoscopic sinus surgery (ESS) is 76-98% effective in improving CRS patients' symptoms.Surgical outcomes can be compromised in the immediate post-operative period by scarring, adhesion formation, and early polyp recurrence.Oral and topical corticosteroid therapy has become integral to the maintenance of successful surgical outcomes, the management of post-operative scarring and edema, and the prevention of nasal polyp recurrence.Steroid-eluting sinus implants have been shown in clinical trials to improve postoperative outcomes after ESS by delivering localized, sustained release of corticosteroids directly onto inflamed sinus tissue.What this study addsThis observational study is one of the first to use real-world evidence to assess the effect of steroid-eluting sinus implants on healthcare resource use (HCRU) in patients with chronic rhinosinusitis who underwent sinus surgery with or without implants.Use of implants significantly reduced HCRU, including all-cause outpatient visits (94.3% vs 96.6%, p < .001), all-cause otolaryngologist visits (47.3% vs 59.6%, p < .001), and all-cause ER/urgent care visits (9.2% vs 11.8%, p = .007), as well as sinus endoscopy (39.1% vs 43.8%, p = .003).Use of implants had no significant effect on sinus procedures such as debridement and polypectomy, as well as sinus-related imaging such as CT, MRI, and x-ray.

Inpatient Constipation Among Migraine Patients Prescribed Anti-calcitonin Gene-Related Peptide Monoclonal Antibodies and Standard of Care Antiepileptic Drugs: A Retrospective Cohort Study in a United States Electronic Health Record Database.

INTRODUCTION: Erenumab, an anti-calcitonin gene-related peptide (CGRP) receptor monoclonal antibody (mAb), was approved by the US Food and Drug Administration in May 2018. Constipation with serious complications was added to the Warning and Precautions section in the erenumab Prescribing Information in October 2019 after events were observed during post-marketing surveillance. We aimed to assess and compare the risk of inpatient constipation, and, separately, inpatient constipation with serious complications, among patients with migraine treated with CGRP mAbs and standard of care antiepileptic drugs (AEDs). METHODS: Within Optum's Electronic Health Record Research Database, patients with migraine who initiated erenumab, other CGRP mAbs, and AEDs were identified from May 2018 through March 2020. Erenumab initiators were propensity score-matched separately to initiators of other CGRP mAbs and AEDs. Incident inpatient constipation events, and serious complications, were identified using multiple risk windows for outcome assessment (30-, 60-, 90-day risk windows, and all available follow-up). Odds ratios (ORs) were calculated comparing inpatient constipation risk among matched erenumab initiators relative to comparators. RESULTS: We identified 17,902 erenumab, 13,404 other CGRP mAb, and 49,497 AED initiators who met study criteria. Among matched initiators, the risk of inpatient constipation was 0.46% (95% confidence interval (CI) 0.35-0.60) for erenumab and 0.44% (95% CI 0.33-0.58) for other CGRP mAbs within the 90-day risk window, with a corresponding OR of 1.06 (95% CI 0.72-1.55). Among matched erenumab and AED initiators, inpatient constipation risk was 0.53% (95% CI 0.42-0.66) and 0.76% (95% CI 0.62-0.92), respectively, and the OR was 0.69 (95% CI 0.51-0.94). Few serious complications were observed. CONCLUSION: Patients initiating erenumab had similar risk of inpatient constipation within 90 days of treatment initiation versus patients initiating other CGRP mAbs, and lower risk versus patients initiating AEDs. These findings provide context to events observed during post-marketing surveillance.

Cardiovascular Risk in Users of Mirabegron Compared with Users of Antimuscarinic Treatments for Overactive Bladder: Findings from a Non-Interventional, Multinational, Cohort Study.

INTRODUCTION: During clinical trials, mirabegron, a ß3-adrenoreceptor agonist, was associated with increased vital signs vs placebo in patients with overactive bladder. OBJECTIVE: The purpose of this study was to compare incidence rates of adverse cardiovascular (CV) outcomes following mirabegron or antimuscarinic use. METHODS: We conducted an observational post-marketing safety study utilising real-world data. The study population was identified within five sources: Danish and Swedish National Registers, Clinical Practice Research Datalink (UK), Optum (USA) and Humana (USA). Episodes of time when patients were new users of mirabegron or antimuscarinics (October 2012-December 2018) were sourced from prescriptions and matched on propensity scores. Occurrences of major adverse cardiovascular events (MACE), acute myocardial infarction (AMI), stroke, CV mortality and all-cause mortality were identified. Outcome incidence rates and hazard ratios from Cox models were estimated. RESULTS: Overall, 152,026 mirabegron and 152,026 antimuscarinic episodes were matched. The population consisted of 63.1% women and 72.6% were ≥ 65 years old. There were no appreciable differences in the incidence rates of MACE, AMI or stroke between users of mirabegron and antimuscarinics. Incidence rates of CV mortality (hazard ratio 0.83, 95% confidence interval 0.73-0.95) and all-cause mortality (hazard ratio 0.80, 95% confidence interval 0.76-0.84) were no higher with mirabegron vs antimuscarinics. Results restricted to episodes at high risk for CV events or stratified by age (< 65 years, ≥ 65 years) or prior overactive bladder medication use were consistent with overall findings. CONCLUSIONS: This large, multinational study found no higher risk of MACE, AMI, stroke, CV mortality or all-cause mortality among users of mirabegron relative to users of antimuscarinics.

During clinical trials, mirabegron, which is a treatment for overactive bladder, was associated with small increases in heart rate and blood pressure. This study was conducted to compare the frequency of cardiac events following the use of mirabegron or antimuscarinics, a group of treatments also used to treat overactive bladder. We obtained the data for this study from four countries: Denmark, Sweden, the UK and the USA. We identified people who were new users of mirabegron or antimuscarinics from 2012 to 2018 using prescription or dispensing records. Occurrences of major cardiac events, heart attack, stroke, death due to cardiac events and death from any cause were evaluated. Overall, we identified 152,026 times when mirabegron or antimuscarinics were each used as new treatments. Most of the people in the study were women (63.1%) and at least 65 years old (72.6%). There were no notable differences between the treatment groups with regard to how often major cardiac events, heart attack or stroke occurred. Further, death due to cardiac events and death from any cause were no higher with mirabegron compared with antimuscarinics. We obtained similar results when the data were assessed for patients who were at high risk for cardiac events or split by age (less than 65 years or at least 65 years) or a history of overactive bladder medication use. In conclusion, this large study involving data from several countries found no higher risk of major cardiac events, heart attack, stroke or death among people prescribed mirabegron compared with antimuscarinics.

A study of cancer occurrence in users of mirabegron and antimuscarinic treatments for overactive bladder.

OBJECTIVE: This post-authorization safety study (EU PAS Register Number: EUPAS16088) was designed to compare the incidence of cancer outcomes in patients treated with mirabegron versus antimuscarinic medications. METHODS: Cohorts of mirabegron initiators during 2012-2018 were propensity-score matched to antimuscarinic medication initiators within real-world data sources (Danish National Registers, Swedish National Registers, Clinical Practice Research Datalink [UK], Optum [US], and Humana [US]). Incident cancer cases were identified during follow-up from direct linkage to cancer registers or validated through medical record review or through physician questionnaires. Comparisons of sex-specific composite cancer outcomes (cancer of the lung/bronchus, colon/rectum, melanoma of skin, urinary bladder, non-Hodgkin lymphoma, kidney/renal pelvis, pancreas, prostate in men and breast and uterus in women) were made overall and for person-time in the first year and after the first year following start of treatment, for all ages and for the subgroup ≥65 years. RESULTS: Among the 80,637 mirabegron initiators matched to 169,885 antimuscarinic medication initiators, 68% were at least 65 years of age and 66% were women. Over 5000 incident cancer cases were observed overall. Incidence rates were higher for men than women for composite and individual cancer outcomes. The pooled fixed effects hazard ratios for composite cancer outcomes (all ages) were 1.05 (95% confidence interval [CI]: 0.98-1.14) for women and 1.06 (95% CI: 0.98-1.14) for men. Results were similar in persons ≥65 years. CONCLUSIONS: The results suggest no association between mirabegron use and risk of cancer, compared with antimuscarinic medications, in either men or women. Registration: EU PAS Register Number: EUPAS16088.

Safety study of live, oral human rotavirus vaccine: A cohort study in United States health insurance plans.

As part of a regulatory commitment for post-licensure safety monitoring of live, oral human rotavirus vaccine (RV1), this study compared the incidence rates (IR) of intussusception, acute lower respiratory tract infection (LRTI) hospitalization, Kawasaki disease, convulsion, and mortality in RV1 recipients versus inactivated poliovirus vaccine (IPV) recipients in concurrent (cIPV) and recent historical (hIPV) comparison cohorts. Vaccine recipients were identified in 2 claims databases from August 2008 - June 2013 (RV1 and cIPV) and January 2004 - July 2008 (hIPV). Outcomes were identified in the 0-59 days following the first 2 vaccine doses. Intussusception, Kawasaki disease, and convulsion were confirmed via medical record review. Outcome IRs were estimated. Incidence rate ratios (IRRs) were obtained from Poisson regression models. A post-hoc self-controlled case series (SCCS) analysis compared convulsion IRs in a 0-7 day post-vaccination period to a 15-30 day post-vaccination period. We identified 57,931 RV1, 173,384 cIPV, and 159,344 hIPV recipients. No increased risks for intussusception, LRTI, Kawasaki disease, or mortality were observed. The convulsion IRRs were elevated following RV1 Dose 1 (cIPV: 2.07, 95% confidence interval [CI]: 1.27 - 3.38; hIPV: 2.05, 95% CI: 1.24 - 3.38), a finding which is inconclusive as it was observed in only one of the claims databases. The IRR following RV1 Dose 1 in the SCCS analysis lacked precision (2.40, 95% CI: 0.73 - 7.86). No increased convulsion risk was observed following RV1 Dose 2. Overall, this study supports the favorable safety profile of RV1. Continued monitoring for safety signals through routine surveillance is needed to ensure vaccine safety.